Project Summary Cryptococcus continues to cause significant disease in immunocompromised individuals, particularly those with HIV/AIDS. Understanding the interplay between the human immune system and this pathogenic fungus is critical if we hope to improve clinical outcomes. The overall scientific objective of the research is to understand how the immune system in humans is directed towards a protective or deleterious response in Cryptococcus infection, while the specific objective of this proposal is to determine factors that impact the helper T cell response in humans during cryptococcal meningitis. Notably, there is particular interest in how the HLA/MHC system influences CD4+ T cells in their response to Cryptococcus. To accomplish this, the first aim is to identify the most prevalent HLA alleles in persons with cryptococcal disease. The hypothesis is that certain HLA alleles are associated with developing progressive disease, while others are associated with attenuating or protecting against disease. Establishing HLA-disease associations not only carries important clinical and therapeutic implications, but creates the knowledge base for further immunological studies. Aim two will use immunophenotyping modalities to determine helper T cell responses in the cryptococcal- specific immune response. The use of CD4+ T cell tetramers on cells from HIV-infected humans provides a proof-of-concept model for the study of infectious disease-specific T cell responses going forward. Additionally, performing activation induced marker (AIM) assays on the same cohort will provide a comparator method in the testing of the hypothesis that Th1 helper T responses are more protective in cryptococcosis than Th2 responses. The data generated by this study will drive innovation in the areas of vaccine development, personalized medicine, and health systems implementation. By establishing the necessary data on HLA prevalence of our study population and successfully implementing our proposed immunology methods to determine disease-specific T cell responses, we will lay the foundation for future clinical and basic science studies to understand how the human immune system responds to infection with Cryptococcus and manipulate that response to reduce disease.